The goal of this project is address a large unmet medical need by providing more kidneys for transplant. For the >400,000 patients with end-stage renal disease in the U.S. the pool of cadaveric kidneys has remained stagnant over the past decade. As a result, the dialysis population is expected to reach >2-million patients in the next decade at an aggregate cost of >$1-trillion USD. We intend to use BREONICS' warm Exsanguinous Metabolic Support (EMS) perfusion technology (32?C) that supports ex vivo oxidative metabolism as the platform to deliver Mesoblast, Inc.'s non-immunogenic mesenchymal precursor cells (MPCs) technology, that is in late Phase clinical trials, to mediate the repair of warm ischemically damaged human kidneys. The combination of EMS technology, that is awaiting FDA approval to begin clinical trials in kidney transplantation, with the MPCs technology to repair ischemically damaged kidneys will provide for significant expansion of the cadaveric renal allograft pool by making it feasible to access cadaveric donors kidneys that today are never considered for transplantation in the U.S. because they are considered to be too damaged. By localizing the MPCs within damaged kidneys during ex vivo EMS perfusion, the repair processes will be potentiated. The targeting of MPCs directly to the kidney will result in higher intrarenal concentrations of the paracrine and endocrine effects than can be achieved with the dilution effects that occur with systemic administration of MPCs. The MPCs will be fluorescently labeled and tested in a paired human kidney model. A dose escalation study will be performed where one kidney will be EMS perfused without stem cells while the paired human kidney will be perfused with the MPCs for 48 hours of ex vivo EMS perfusion. Evaluation of the repair potential will include: the extent and reversibility of proteinuria to identify the loss/recvery of cell surface polarity, glomerular filtration rate, DNA synthesis, cytoskeletal regeneration, chemokine/cytokine synthesis and histologic evaluations. Once the optimized dose of MPCs per gram of kidney is identified, we will perform in- depth studies to more fully characterize the repair processes for the human kidneys using the labeled MPCs to determine deposition and any retention within the renal parenchyma, synthesis, renal markers of injury/repair and characterization of the recovered MPCs following perfusion to determine the phenotype and synthetic functions following the 48 hours of EMS perfusion of the human kidneys. Significant to our project is the observation that MPCs mediated paracrine effects occur within 48 hours, a period that corresponds to our proposed 48 hours of ex vivo EMS perfusion. Mesoblast, Inc. a public company is well positioned to commercialize the technology developed from this project. We believe an allograft treated with MPCs will obtain regulatory approval as transplantable because the MPCs are not immunogenic, do not integrate or survive within the body, do not form teratomas and have an established safety profile. If successful this approach to expanding organ donor criteria will positively impact the organ shortage.